A possible relationship between the renin-angiotensin-aldosterone system and the complications of diabetes mellitus has not been investigated previously. Preliminary results from this laboratory suggest 1) that rats rendered diabetic by alloxan develop hypertension and have decreased renin activity and angiotensin II, 2) that in some humans with diabetes mellitus of long duration, the plasma renin activity is decreased, 3) that decreased plasma renin activity is associated with the two complications of diabetes mellitus thus far studied, namely, neovascularization of the optic fundi and orthostatic hypotension, and 4) that oral hypoglycemic agents may increase plasma renin activity. The objectives of this research are threefold: 1) to extend previous studies from this laboratory using the alloxan diabetic rat and other diabetic rat models with special emphasis on defining the mechanisms of decreased renin activity and angiotensin, renin release, and hypertension; 2) to define the relationships among renin activity, renin substrate, angiotensin II, aldosterone, glucose, sodium and blood volume in patients with diabetes mellitus and to relate these parameters to observed complications of diabetes mellitus in humans; and 3) to assess the effect of oral hypoglycemic agents on renin substrate, renin activty, angiotensin II, and blood pressure in both human and rat. The data collected will be analyzed so as 1) to define the relationship between the renin-angiotensin-aldosterone system and complications of diabetes mellitus especially as related to the hypertension, orthostatic hypotension, cardiac disease, renal disease, and small vessel disease in both human and experimental diabetes mellitus, and 2) to further define the basic physiology and pathophysiology of the renin-angiotensin-aldosterone system.